Down syndrome and postoperative hemodynamics in patients undergoing surgery for congenital cardiac communications

Although Down syndrome (DS) is considered a risk factor for hemodynamic instabilities (mainly pulmonary hypertension–PH) following surgery for congenital cardiac communications, many DS patients do surprising well postoperatively. We prospectively analyzed perioperative factors for a possible correlation with post-cardiopulmonary bypass (CPB) inflammatory reaction and postoperative PH in pediatric subjects. Sixty patients were enrolled (age 3 to 35 months), 39 of them with DS. Clinical and echocardiographic parameters (anatomical and hemodynamic) were computed preoperatively. Pulmonary and systemic mean arterial pressures (PAP and SAP) were assessed invasively intra and postoperatively. Immediate postoperative PAP/SAP ratio (PAP/SAPIPO) and the behavior of pressure curves were selected as primary outcome. Serum levels of 36 inflammatory proteins were measured by chemiluminescence preoperatively and 4 h post CPB. Of all factors analyzed, peripheral oxygen saturation (O2Sat, bedside assessment) was the only preoperative predictor of PAP/SAPIPO at multivariate analysis (p = 0.007). Respective values in non-DS, DS/O2Sat ≥ 95% and DS/O2Sat < 95% subgroups were 0.34 (0.017), 0.40 (0.027) and 0.45 (0.026), mean (SE), p = 0.004. The difference between non-DS and DS groups regarding postoperative PAP curves (upward shift in DS patients, p = 0.015) became nonsignificant (p = 0.114) after adjustment for preoperative O2Sat. Post-CPB levels of at least 5 cytokines were higher in patients with O2Sat < 95% versus those at or above this level, even within the DS group (p < 0.05). Thus, a baseline O2Sat < 95% representing pathophysiological phenomena in the airways and the distal lung, rather than DS in a broad sense, seems to be associated with post-CPB inflammation and postoperative PH in these patients.


Patients
This was a prospective cohort study comprising patients who were referred to the Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil from November 2016 to September 2021, for surgical repair of congenital cardiac communications.Patients entered the study consecutively if they met the following inclusion criteria: age 1 month to 3 years; biventricular cardiac physiology; presence of at least one unrestrictive post-tricuspid cardiac communication (diameter of the communication greater than 50% of the aortic annulus diameter) without pulmonary stenosis; and clinical and echocardiographic signs of at least moderately elevated pulmonary arterial pressure (preferably with a systolic pulmonary arterial pressure > 40 mmHg whenever parameter obtainment was possible); The exclusion criteria were: presence of extracardiac syndromes other than Down syndrome; complex cardiac anomalies, including those anatomically or physiologically characterized as univentricular hearts; predominant right-to-left intracardiac shunting, suggesting high pulmonary vascular resistance associated with advanced pulmonary vasculopathy; presence of any signs of ongoing or recent inflammatory or infectious diseases; and reoperation.The Heart Institute is a tertiary referral center.A great percentage of its pediatric patient population is represented by neonates, subjects with complex cardiac anomalies and candidates to reoperation.In this way, although this study was initially planned to include patients aged 1 month to 2 years, we needed to consider an extended age range (up to 3 years) in order to have an adequately sized study population.Forty-seven healthy pediatric subjects (including 24 nonsyndromic subjects aged 1 to 27 months) entered the study as controls for the laboratory determinations of inflammatory mediators.This group was also made up of individuals with Down syndrome (23 subjects aged 1 to 35 months).Nonsyndromic and syndromic individuals included for this specific purpose were from the same geographic area as that of the patients.They did not have any relevant hemodynamic abnormalities or signs of pulmonary hypertension upon evaluation by the Heart Institute team.Data from the control group were used only for descriptive purposes.They were not included in inferential analysis.All participants were included after obtainment of a written informed consent from their parents.All procedures of the study were approved by the ethics committee of the Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil (approval number: 2.068.696).The authors also confirm that the entire research was performed in accordance with the Declaration of Helsinki.

Preoperative evaluation and perioperative management
Diagnostic evaluation consisted of a detailed clinical history, physical examination, chest radiographs, electrocardiogram and a transthoracic echocardiogram.The diagnosis of Down syndrome was based on phenotypic features and was confirmed by genetic testing.Patients were evaluated for the presence or absence of clinical features suggestive of pulmonary overcirculation: dyspnea, congestive heart failure and failure to thrive.Transthoracic echocardiography was used to assess cardiovascular anatomy and hemodynamic parameters.Systolic pulmonary arterial pressure and mean pulmonary arterial pressure were estimated in patients for whom reliable curves of tricuspid and pulmonary regurgitation jets (respectively) could be obtained.Some patients presented

Postoperative events as secondary outcome
We defined cardiovascular (hemodynamic) and respiratory events beyond the concept of pulmonary hypertensive crises, encompassing the following instabilities: 1, typical pulmonary hypertensive crises defined as sustained elevation of pulmonary arterial pressure (pulmonary/systemic mean arterial pressure ratio > 0.75) with a decline in systemic pressure (≥ 20%) and peripheral oxygen saturation (< 90%) 16 ; 2, systemic hypotension with a pulmonary/systemic mean arterial pressure ratio in the range of 0.50-0.75requiring frequent changes in the doses of vasoactive drugs; 3, prolonged and/or recurrent hemodynamic and respiratory disturbances not reverted by sedation and manual ventilation; and 4, all critical instabilities requiring cardiorespiratory resuscitation.Elevations of pulmonary arterial pressure, even to suprasystemic levels, that were rapidly reverted by sedation and manual ventilation were not characterized as events.Interpretations were made independently by 3 observes (ESC and AAL, co-authors, and on-duty intensivist).

Statistical analysis
The sample size was calculated to demonstrate statistically significant differences in the parameter PAP/SAP IPO between the study groups.In order to compare 2 groups (i.e., Down-syndrome versus non-Down syndrome patients), a total of 50 patients was considered sufficient to demonstrate a standardized difference of approximately 1.05 SD (power 95.4%, significance level 0.05 Unless otherwise specified, numeric variables are presented as medians with interquartile ranges.Categorical variables are presented as number of cases and percentages.In descriptive analyses, comparisons between groups were performed using the Mann-Whitney test and Kruskal-Wallis test.Differences involving categorical variables were tested using the Chi-square family of tests.The Wilcoxon test and Pearson's coefficient of correlation were used to test for differences and associations within subjects.Inferential statistics was used to analyze outcomes and their predictors.All dependent variables were tested for closeness to the normal (Gaussian) distribution.In most instances, closeness to the normal distribution was obtained using the Box-Cox transformation of dependent variables.Hemodynamic outcomes were analyzed in patient groups using the general linear model (one-way GLM analysis or two-way GLM analysis for repeated measures).Predictors of postoperative events (categorical outcome) were analyzed using logistic regression analysis.In view of the complex distributions observed for most biological markers (inflammatory proteins), we opted to compare groups using nonparametric statistics (Mann-Whitney test).In all tests, 0.05 was set as the significance level.In all parametric and nonparametric procedures aimed at comparing more than two groups, significance values were adjusted using the Bonferroni correction for multiple tests.Statistical analysis was performed using the SPSS statistical software, version 28 (IBM, Armonk, NY, USA).

Ethical approval and consent to participate
The study protocol was approved by the Institutional Scientific and Ethics Committee, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil, approval N o .2.068.696.Informed consent was obtained from the patient's parents before enrollment in the study.

Results
Sixty patients were enrolled with age range of 3 to 35 months.Thirty-nine of them had Down syndrome.Demographic and diagnostic data of syndromic and nonsyndromic individuals are shown in Table 1.All but one patient had unrestrictive ventricular septal defect or complete atrioventricular septal defect either isolated or associated with atrial septal defect (secundum type) or patent ductus arteriosus.In the present cohort, atrioventricular septal defects were present in syndromic individuals only.All but one patient presenting with peripheral oxygen saturation < 95% were syndromic individuals with atrioventricular septal defect (n = 19).However, there were patients with Down syndrome presenting with normal oxygen saturation as well (n = 20, 5 with atrioventricular canal).Syndromic patients had lower levels of systemic arterial pressure compared to nonsyndromic ones.Seven patients underwent preoperative cardiac catheterization.All of them were Down syndrome individuals presenting with no evident signs of congestive failure.Peripheral oxygen saturation in this subgroup was 90% (89-96%) (median with interquartile range) compared with 96% (94-98%) in patients not requiring cardiac catheterization (p = 0.030).Despite that, pulmonary vascular resistance was found to be only mildly elevated (3.8 [3.0-4.9]Wood units x m 2 ) with a decrease following nitric oxide inhalation (3.4 [1.5-4.3]Wood units x m 2 , p = 0.043), thus allowing for safe assignment to cardiac surgery.
Postoperative hemodynamics was analyzed first by obtaining the parameter PAP/SAP IPO .In the entire patient population, PAP/SAP IPO ranged from 0.19 to 0.74 (0.37 [0.32-0.46]).Greater values were seen in patients with Down syndrome compared to nonsyndromic individuals (respectively, 0.40 [0.33-0.49]and 0.34 [0.29-0.42],p = 0.005).Values were even greater in the subgroup of patients requiring preoperative cardiac catheterization (0.54 [0.47-0.62]compared with 0.36 [0.32-0.44] in subjects not requiring catheterization, p = 0.002).Subsequent analysis of preoperative and intraoperative variables to identify possible associations with PAP/SAP IPO showed several potential predictors in addition to Down syndrome (Table 2).However, only preoperative peripheral oxygen saturation measured at bedside and pre-cardiopulmonary bypass PAP/SAP ratio computed in the operating room remained in the final multivariate statistical model (Table 2).
The role of Down syndrome, type of cardiac anomaly and baseline oxygen saturation in predicting postoperative hemodynamics was further investigated using bivariate analysis as illustrated in Fig. 1.The difference between syndromic and nonsyndromic individuals with respect to PAP/SAP IPO became statistically nonsignificant when means were adjusted for oxygen saturation (Fig. 1A,B).The greatest values of PAP/SAP IPO were actually seen in Down syndrome patients presenting with peripheral oxygen saturation < 95% (Fig. 1D).Although the type of cardiac anomaly could be looked on as an important predictor (Fig. 1C), the difference between groups became nonsignificant when baseline oxygen saturation (lowest levels observed in subjects with atrioventricular septal defect, Fig. 1E) was taken into consideration (Fig. 1F).Thus, oxygen saturation was characterized as the most important preoperative predictor of postoperative hemodynamics.In patients with Down syndrome versus nonsyndromic ones, the risk of having a PAP/SAP IPO > 0.40, which may be looked on as an important elevation www.nature.com/scientificreports/ of pulmonary artery pressure postoperatively, was 2.62 (0.85-8.20) (odds ratio with 95% CI p = 0.095).However, in patients with baseline oxygen saturation < 95% versus those who were at or above this level, the risk was 5.44 (1.69-17.57)(p = 0.005).Each 1% reduction in preoperative oxygen saturation was associated with an increase of 0.015 in PAP/SAP IPO (p < 0.001).Hemodynamics was also analyzed by examining pulmonary and systemic arterial pressure curves.Figure 2 shows pressure and oxygen saturation curves for patients with and without Down syndrome.While pulmonary artery pressure remained relatively stable with higher levels in syndromic individuals (Fig. 2A), systemic arterial pressure tended to decline initially, with no difference between groups (Fig. 2C).Lower but not statistically different oxygen saturation levels were computed for Down syndrome patients (Fig. 2E).However, and again when curves were normalized by adjusting for baseline (preoperative) oxygen saturation, between-group differences became unimpressive for all three parameters (Fig. 2B,D,F).
Analysis of all 36 inflammatory markers, at baseline, showed differences between patients and controls only for complement components C5/C5a.Levels in controls, nonsyndromic patients, syndromic patients with oxygen saturation ≥ 95% and syndromic patients with oxygen saturation < 95% were 1776 (842-3954) upi, 2225 (1302-6005) upi, 2842 (810-6089) upi and 4644 (2456-8159) upi respectively, with a significant difference between the former group and the latter (p = 0.014).Levels in the latter group were also higher when compared to the subgroup of controls without Down syndrome (4644 [2456-8159] upi and 1820 [1144-4550] upi respectively, p = 0.009).For the entire patient population, there was a negative correlation between serum C5/C5a and bedside oxygen saturation (r = −0.37,p = 0.009).Analysis of inflammatory markers within the group of surgical patients showed no differences between syndromic and nonsyndromic individuals.Data analysis within the controls showed a single difference between syndromic and nonsyndromic subjects, with higher levels of ICAM-1 in the former group (respectively, 48105 [37169-52844] upi and 38765 [30290-43647] upi, p = 0.005).
Cardiopulmonary bypass was followed by changes in hematological parameters.Compared to baseline, there was a 67% decrease in lymphocyte count, a 46% increase in monocytes and a 2.3-fold increase in neutrophils with a 10.9-fold increase in neutrophil-to-lymphocyte ratio (p < 0.001 for all comparisons).Besides, there was a marked decrease in platelet count (58%, p < 0.001) with no immediate change in platelet volume.The systemic Table 1.Demographic and diagnostic data in patient groups.Numeric variables are presented as medians with interquartile ranges.Differences were tested using the Mann-Whitney test.For categorical variables, differences were analyzed using the Chi-square family of tests.*A, presence of clinical features suggestive of pulmonary overcirculation (dyspnea, congestive heart failure, and failure to thrive); B, absence of such features, thus suggesting elevation of pulmonary vascular resistance.† Due to technical limitations, reliable data were obtained in 28 syndromic and 6 non syndromic patients.‡ Reliable data were available from 12 syndromic and 16 nonsyndromic individuals.§ Values < 20 cm indicate absence of pulmonary overcirculation, and are generally associated with heightened pulmonary vascular resistance in pediatric patients with unrestrictive cardiac communications.ǁTricuspid annular plane systolic excursion is a parameter directly related to right ventricular systolic function.www.nature.com/scientificreports/inflammatory reaction was also characterized by changes in serum levels of inflammatory proteins as shown in Table 3.While several proteins increased from baseline, others decreased (C5/C5a, CD40L, GRO alpha, Serpin-E1 and RANTES).The decrease in serum RANTES was directly correlated with the amount of vasoactive/inotropic drugs required to stabilize post-cardiopulmonary bypass hemodynamics (expressed as vasoactive-inotropic score, r = 0.43, p = 0.002), probably reflecting the reduction and functional exhaustion of T lymphocytes.Postcardiopulmonary bypass level of CD40L was directly correlated with platelet count (r = 0.34, p = 0.019).At preliminary analysis, Down syndrome patients seemed to have higher postoperative levels of inflammatory proteins compared to nonsyndromic ones.Respective levels for IL-6 were 1791 (836-2755) upi and 1010 (368-1288) upi (p = 0.017); for IP-10, levels were 2353 (1010-5878) upi and 936 (362-1574) upi (p = 0.004).However, subsequent analyses showed that the magnitude of post-cardiopulmonary bypass inflammatory reaction was in fact more closely related to baseline oxygen saturation as illustrated in Figs. 3, 4. Considering the 13 proteins whose levels changed postoperatively relative to baseline (Table 3), significant correlations between postoperative levels and cardiopulmonary bypass duration was observed only for IL-6 (r s = 0.32, p = 0.033), IP-10 (r s = 0.35, p = 0.020) and IL-1RA (r s = 0.29, p = 0.038).
During the intensive care unit stay, 14 patients had clinical events characterized by interrelated hemodynamic and respiratory instabilities as defined.The occurrence of such instabilities had a direct impact on the duration of mechanical ventilation (p < 0.001).Postoperative events could not be predicted on the basis of any preoperative parameters.In particular, events occurred in 9 Down syndrome patients (23%) and 5 nonsyndromic individuals (24%) (p = 0.999).However, events could be effectively predicted based on post-cardiopulmonary bypass mean systemic arterial pressure measured in the operating room, which was characterized as a protective factor (odds ratio 0.46 for quartiles, 95% CI 0.24-0.89,p = 0.021) and PAP/SAP IPO , identified as a risk factor (odds ratio 2.62 for quartiles, 95% CI 1.32-5.20,p = 0.006).Thus, preoperative oxygen saturation played and indirect role in determining the risk of postoperative events.One patient died of rapid-onset systemic hypotension and bradycardia unresponsive to vasopressin and other life-supporting procedures.Another patient died of septicemia.

Discussion
The present study was focused on hemodynamic instabilities and clinical events following surgery for congenital cardiac communications.To investigate the role of Down syndrome and other clinical features in predisposing patients to such instabilities, the PAP/SAP IPO parameter and the behavior of pulmonary and systemic pressure curves were used as primary endpoint.In the present cohort, comprising patients for the majority of whom preoperative cardiac catheterization was not required, peripheral oxygen saturation measured at bedside was found to be the best predictor of postoperative hemodynamics.This was demonstrated by adjusting two different statistical models to the observed data, i.e., the general linear model using a single outcome measure per patient (PAP/SAP IPO ), and the repeated-measures general linear model using the pulmonary artery pressure curve as outcome.In both instances, preoperative oxygen saturation was analyzed as a covariate in the model.At first sight, Down syndrome and the presence of atrioventricular septal defect seemed to be associated with Table 2. Factors influencing early postoperative hemodynamics*.CPB cardiopulmonary bypass, PAP and SAP respectively, mean pulmonary arterial pressure and mean systemic arterial pressure, PAP/SAP pulmonary/systemic mean arterial pressure ratio, TAPSE tricuspid annular plane systolic excursion.*Defined as immediate postoperative pulmonary/systemic mean arterial pressure ratio (PAP/SAPIPO, mean of first 4 values, readings at 2 h intervals).Factors and covariates were analyzed using the General Linear Model after Box-Cox transformation of the dependent variable (PAP/SAPIPO).† Stepwise procedure for variable selection using alpha of 0.15 to enter and to remove variables.‡ Same procedure using alpha of 0.10 to enter and to remove variables.§ Transthoracic echocardiography.ǁVelocity-time integral of blood flow in pulmonary veins (transthoracic echocardiography) is directly related to the magnitude of pulmonary blood flow.**Tricuspid annular plane systolic excursion is a parameter directly related with right ventricular systolic function.www.nature.com/scientificreports/altered hemodynamics as well.This apparent association was probably due to the fact that the lowest preoperative levels of oxygen saturation were detected in syndromic individuals with atrioventricular canal.Noticeably, however, several syndromic patients, some with atrioventricular septal defect had normal preoperative oxygen saturation and did quite well postoperatively.Thus, within the limits of cardiac anomalies we diagnosed in the present cohort, the presence of Down syndrome itself did not seem to influence postoperative hemodynamics.So, the next question is what lies behind decreased levels of oxygen saturation, which are quite frequent in Down syndrome individuals, that renders patients with unrestrictive cardiac communications at increased risk for postoperative instabilities, i.e., pulmonary hypertension.The idea that comes first is that decreased oxygen saturation is due to right-to-left intracardiac shunting associated with increased pulmonary vascular resistance.Although pulmonary vascular remodeling sounds like www.nature.com/scientificreports/an obvious explanation for altered postoperative hemodynamics in these patients, critical levels of pulmonary vascular resistance associated with advanced pulmonary vasculopathy did not seem to constitute the pathophysiological scenario in the present cohort.In fact, the pulmonary-to-systemic blood flow ratio measured by transthoracic echocardiography in 19 patients with Down syndrome, atrioventricular septal defect and peripheral oxygen saturation lower than 95% was 2.20 (1.80-2.90).Moreover, only mildly elevated pulmonary vascular resistance was observed in patients who underwent preoperative cardiac catheterization.A more complete explanation for the association between preoperative oxygen desaturation and altered postoperative hemodynamics should include abnormalities such as intrapulmonary in addition to intracardiac shunting, ventilation-perfusions mismatch of several causes and endothelial dysfunction with vasoconstriction in addition to vascular cell proliferation with remodeling of pulmonary arteries 17 .In the particular setting of Down syndrome, a number of congenital and acquired airway and pulmonary conditions may contribute to intermittent or sustained hypoxia leading to regional or global pulmonary vasoconstriction aggravated by hemodynamic stress (congenital heart defects), endothelial dysfunction and inflammation 18 .Thus, rather than a simple result of right-to-left intracardiac shunting, systemic oxygen desaturation should be looked on as a consequence of several morbid conditions, many with a potential for persistence even after successful cardiac surgery, serving as a pathophysiological basis for hemodynamic instabilities.Another point to be addressed in this context, is the biological crosstalk between elements of small airways and vessels in the lungs.These structures are inserted in the indivisible microenvironment of the distal lung in such a way that biological phenomena occurring on one side (airways or vessels) have inevitable effects on the other 19 .Viral respiratory infections, which are very frequent and recurrent in pediatric subjects with congenital cardiac shunts, may be taken as an example of this situation.Respiratory epithelial cells infected by viruses express a number of cytokines, chemokines, growth factors and related molecules that are central to the pathophysiology of bronchiolitis and asthma 20,21 .The majority of such molecules were also shown to play a pivotal role in pulmonary vascular remodeling.For example, chemokine RANTES (regulated on activation, normal T-cell expressed and secreted) is highly expressed during infections by respiratory syncytial virus, rhinovirus and other agents 22,23 , and was shown to be upregulated, along with its receptor, in the endothelium of pulmonary arterial hypertensive patients 24,25 .Rhinovirus was also shown to induce the expression of chemokine IP-10 (interferon-gamma-inducible protein 10) which plays a central role in vascular smooth muscle cell proliferation and pulmonary arterial remodeling 9,10,26 .Thus, airway and vascular remodeling are closely related processes in Table 3. Serum levels of inflammatory mediators at baseline and 4 h after cardiopulmonary bypass termination.Levels of inflammatory proteins were determined as units of pixel intensity (upi, chemiluninescence) and are presented as medians with interquartile ranges.Differences were analyzed using the Wilcoxon test.the lungs.In a recent study of ours, the presence of genetic material for respiratory viruses in tracheal aspirates of pediatric patients undergoing surgery for congenital cardiac shunts was found to be a risk factor for heightened pulmonary arterial pressure postoperatively 27 .

Multivariate
In the present study, serum levels of several inflammatory proteins increased postoperatively compared to baseline, largely reflecting the systemic inflammatory reaction that follows the use of cardiopulmonary bypass, while the levels of other proteins decreased.In two instances, there were reasons for the observed decrease.The level of chemokine RANTES was influenced by the use of inotropic and vasoactive drugs which is generally associated with depletion of T lymphocytes.The decrease in CD40L may be explained, at least in part, by the marked reduction in platelet count, since platelets are a major source of CD40L in circulation.Interestingly, postoperative levels of some inflammatory markers were higher in patients presenting with baseline oxygen saturation lower than 95% compared to those who were at or above this level.Importantly, this was also seen within the group of Down syndrome patients.The possibility exists that mechanisms involving proinflammatory pathways are triggered preoperatively and become exacerbated under perioperative stimuli.The observation of normal baseline levels for almost all inflammatory proteins was not surprising, since determinations were performed in serum, not at tissue level.The duration of cardiopulmonary bypass could not totally explain the observed changes in ), interferon gamma-induced protein 10 (IP-10), stromal cell-derived factor 1 (SDF-1) and complement components 5/5a (C5/C5a).Protein levels were determined as units of pixel intensity (upi) and results are presented as geometric means with 95% CI.The Mann-Whitney test was used for all comparisons.serum proteins.Because nearly all of the aforementioned proteins were shown to be involved in pulmonary vascular remodeling [28][29][30] , we speculate that the acute inflammatory storm may also have more prolonged biological effects on pulmonary vessels as to cause persistent hemodynamic alterations late after surgery 31 .Considering the Down syndrome group specifically, the observed associations of baseline oxygen saturation with postoperative inflammation and hemodynamics suggests the existence of a particular subset of high-risk individuals potentially identifiable at preoperative bedside examination.
The study has obvious limitations, some deserving consideration.Our observations cannot be extrapolated to neonates and infants with more complex cardiac anomalies.Although these are extremely important subsets of patients in terms of postoperative complications and management, we felt that their inclusion would increase considerably the complexity of the study, making it difficult to come to simple and useful conclusions.Besides, in view of the limitations of transthoracic echocardiography in providing hemodynamic parameters in some instances, we could not have a complete noninvasive preoperative evaluation in some patients.Right heart catheterization could be the solution but currently, it has restricted indications in this population.So, the hemodynamic profile of our patients was defined by directly measuring pulmonary and systemic arterial pressures in the Based on our data, we would like to conclude that the presence of Down syndrome itself does not necessarily constitute a risk factor for postoperative hemodynamic instabilities in patients undergoing surgery for congenital cardiac communications.Rather, decreased oxygen saturation, which is quite frequent in Down syndrome individuals, seems to be the tip of the iceberg over a number of pathophysiological phenomena with potential impact on postoperative hemodynamics.The risk of having high levels of pulmonary artery pressure postoperatively seems to be 5 times greater in patients with a preoperative peripheral oxygen saturation < 95% compared to those who are above this level.Although further studies are required to better understand how initial pathophysiological phenomena leading to altered oxygen saturation influence the inflammatory response to surgery, as suggested by our results, it is reasonable to suppose that acute inflammation acts in combination with preoperative changes in pulmonary microenvironment to determine the abnormal response of the pulmonary (and systemic) circulation postoperatively.

Figure 1 .
Figure 1.Role of Down syndrome, type of cardiac anomaly and preoperative peripheral oxygen saturation (O 2 Sat) on early postoperative hemodynamics (PAP/SAP IPO , pulmonary/systemic mean arterial pressure ratio, mean of first four values computed in the intensive care unit, readings at 2 h intervals).Analyses were performed using the general linear model after Box-Cox transformation of the dependent variable.Results are presented as means with SE (A,C-E) or adjusted means with SE after inclusion of baseline oxygen saturation as a covariate in the statistical model (B,F with covariate p values of 0.006 and 0.005, respectively).In (C-E) groups not sharing the same letter were different (post-hoc multiple comparisons).AVSD atrioventricular septal defect, VSD ventricular septal defect.

Figure 2 .
Figure 2. Mean pulmonary and systemic arterial pressure (respectively, PAP and SAP) and peripheral oxygen saturation (O 2 Sat) computed during the first 12 h of postoperative intensive care for patients with (squares, n = 39) and without (circles, n = 21) Down syndrome.Data were analyzed using the general linear model for repeated measures after Box-Cox transformation of the dependent variable.Results are presented as means with SE (A,C,E) or adjusted means with SE using baseline oxygen saturation as a covariate in the model (B, D,F, p < 0.05 for the covariate in all tests).

Figure 3 .
Figure 3. Serum levels of inflammatory mediators 4 h after weaning from cardiopulmonary bypass in patients with preoperative peripheral oxygen saturation (O 2 Sat) < 95% (n = 20) compared to those who were at or above this level (n = 40).Shown are the levels of interleukins 6 and 16 (IL-6 and IL-16), interferon gamma-induced protein 10 (IP-10), stromal cell-derived factor 1 (SDF-1) and complement components 5/5a (C5/C5a).Protein levels were determined as units of pixel intensity (upi) and results are presented as geometric means with 95% CI.The Mann-Whitney test was used for all comparisons.

Figure 4 .
Figure 4. Post-cardiopulmonary bypass serum levels of inflammatory proteins for the specific group of patients with Down syndrome.Comparisons were made between patients with preoperative peripheral oxygen saturation (O 2 Sat) < 95% (n = 19) and those who were at or above this level (n = 20).Shown are the levels of interleukins 8 and 16 (IL-8 and IL-16), interferon gamma-induced protein 10 (IP-10), stromal cell-derived factor 1 (SDF-1), complement components 5/5a (C5/C5a) and macrophage inflammatory protein 1 alpha and beta (MIP-1alpha and MIP-1beta).Results are presented as geometric means with 95% CI.Differences were tested using the Mann-Whitney test.